ABSTRACT of SBIR P1 proposal 1R43NS108852-01(Funded Sep 15, 2018) More than a million Americans are afflicted with Parkinson?s disease (PD), a debilitating neurodegenerative disorder. As a result of a progressive and substantial loss of dopaminergic neurons in the substantia nigra compacta, PD patients suffer from severe neurological deficits that can become incapacitating within 10-20 years of diagnosis. Existing PD treatments focus on alleviating motor symptoms by compensating for neurochemical deficits, but such treatment fails to halt the progression of the disease. The discouraging lack of effective neuroprotective drugs is primarily attributed to a limited understanding of the complex mechanisms underlying the degeneration of the nigral dopaminergic system; and, although mitochondrial dysfunction is recognized as the overriding pathophysiological hallmark of PD, no effective treatment options are available to improve mitochondrial function. Metformin (Met), an FDA-approved anti-diabetic drug with an extraordinary safety profile, was recently found to influence metabolic and cellular processes associated with aging and the development of neurodegenerative disease. Unfortunately, the potential utility of Met as a mitochondria-targeting therapeutic is limited by the drug?s chemical properties at physiological pH where it exists as a hydrophilic cation that enters mitochondria rather inefficiently. Notably, our research team was able to increase the mitochondrial concentration of Met 100 to 1000-fold by attaching a lipophilic cation, triphenyl phosphonium (TPP+).1-3 The novel compound, a mitochondria-targeted metformin called MitoMet, is a promising candidate for a drug development program focused on generating treatments for aging-related disorders and diseases attributable to mitochondrial dysfunction. Our preliminary studies revealed two exciting properties of MitoMet: It is brain bioavailable and it leads to substantially higher mitochondrial biogenesis (>100-fold) than unmodified Met in cell culture and animal model studies. Thus, the overarching hypothesis of our SBIR Phase I proposal is that our Met analog, MitoMet, will provide neuroprotective benefit for treatment of Parkinson?s disease due to its ability to activate a bioenergy-sensing, survival signaling pathway (PKD1/AMPK) that regulates mitochondrial biogenesis. This Phase 1 SBIR proposal will pursue two specific aims designed to test this hypothesis. In Aim 1, we will perform detailed pharmacokinetic and target engagement studies to determine the appropriate dose, dosing intervals, and pharmacological properties of MitoMet ? these will serve as the foundation for detailed, in vivo, efficacy studies (preclinical) to be conducted in Phase 2. In Aim 2, we will perform a trio of studies to further assess the drug-like properties of MitoMet metabolite stability, Pharma-ADME fingerprint and repeat-dose toxicology. In terms of the overall impact of our studies, we expect to improve the quality of life for PD patients by developing a therapeutic that improves mitochondrial function. Notably, the high safety profile of the FDA-approved parent molecule, Metformin, should facilitate our ability to bring this novel neuro-restorative drug to market more quickly.